Substituted aminopyrrolecarboxylic acids and esters



United States Patent- O SUBSTITUTED AMINQPYRROLECARBOXYLIC ACIDS AND ESTERS Coy W. Waller, Nanuet, N. Y., and Martin J. Weiss, Highland Park, and John S. Webb, Warren Township, Somerset County, N. J., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application April 19, 1954, Serial No. 424,264

8 Claims. (Cl. 260326.3)

This invention relates to new organic compounds. More particularly, it relates to substituted aminopyrroles and their preparation.

For many years .a study of pyrrole chemistry has been carried out by numerous investigators because of the presence of this heterocyclic nucleus in the structures of haemoglobin and chlorophyll. During the course of this work many pyrrole compounds have been described bearing various substituents. However, the present compounds, 1 alkyl-4-substituted amino-Z-pyrrolecarboxylic acids and esters, have not been described.

The compounds of the present invention may be illustrated by the following structural formula:

in which R is an alkyl radical, R is an amidino, amidinoamidino, aminoacetimidoyl, thiocarbamoyl, S-alkylisothiocarbamoyl, alkyl, nitroaryl, carbobenzoxy or aryl sulfonyl radical and Z is a hydroxyl or alkoxyl radical. Since many of these compounds contain both amino and carboxylic acid radicals, obviously they form salts and esters which are intended to be included within the scope of this invention.

The compounds of the present invention are, in general, crystalline solids with relatively high melting points. They are soluble in the usual organic solvents such as alcohol, pyridine, dimethylformamide etc. In the form of their salts they are water soluble.

I These compounds can be prepared by difierent methodsf One method is by reduction of the corresponding nitro compounds described and claimed in our copending applications, Serial Numbers 424,261 and 424,263, both filed April 19, 1954.

We have found that compounds of the following structure have antibacterial properties.

Y( CH2) C-NH V 11- N 0 ON it C O-amino acid antibacterial substances. The compounds also show analgesic activity.

EXAMPLE 1 4-benzenesulfonamid0-1-methyl-2-pyrr0lecarboxylic acid Sodium methylate parts) is dissolved in ethanol (1120 parts), the solution is cooled to 25 C., ethyl 4- nitro-2-pyrrolecarboxylate (402 parts) is added and then methyliodide (1070 parts) is added. Within a short time heat is evolved and it is necessary to periodically cool the solution in an ice bath to keep the temperature below 40 C. Crystalline solids begin to precipitate and the reaction mixture is allowed to set overnight at room temperature. After chilling and filtering, the collected solids are washed thoroughly with water to remove much of the color. After drying to constant weight in the oven at 55 C., 384 parts (89%) of ethyl l-methyl-4- nitro-2-pyrrolecarboxylate is obtained as light tan colored platelets, melting at lO8-l12 C. Several recrystallizations from ethanol and treatment with activated charcoal give White platelets, melting at 113.2114.2 C. Additional crude material may be obtained by diluting the original mother liquor with Water.

To a hot solution of sodium hydroxide (200 parts) in water (800 parts) a suspension of ethyl 1-niethyl-4-nitro- 2-pyrrolecarboxylate (364 parts) in hot ethanol (640 parts) is added. The yellow solid which forms is dissolved by heating the solvent to reflux and adding water (200 parts). Refiuxing is continued for four and onehalf hours. After then standing overnight at room temperature, coarse. yellow crystals form. These are dissolved by the addition of hot water (2000 parts) and then this solution is acidified with excess 6N hydro-- chloric acid. The suspension is chilled and the crystalline solids are filtered. After drying in the oven at 55 C., to constant weight, 257 parts (82%) of 1-methyl-4-nitro- 2-pyrrolecarboxylic acid, melting point 194-l97 C., are obtained. Several recrystallizations from ethanol and from mixtures of ethanol with water and one treatment with activated charcoal give white crystals, melting at 195l97 C.

1-methyl-4-nitro-2-pyrrolecarboxylic acid (5.0 parts) is hydrogenated with 10% palladium-carbon catalyst (1.5 parts) in ethanol (106 parts) in the Parr low pressure hydrogenation apparatus. The hydrogen uptake is rapid.

The hydrogenation flask is flushed with nitrogen and the:

catalyst is filtered in a nitrogen atmosphere; concentrated sulfuric acid (1.08 parts), is then added dropwise to the chilled filtrate. This gives a white crystalline material which is filtered and air dried to yield 2.5 parts of.4-:

dryness using a Megavac pump with a Dry Ice trap con- The residue is dissolved in 300 parts of boiling;

denser. methanol under nitrogen, filtered and concentrated to 50 parts by volume under reduced pressure. The product crystallizes on cooling overnight. The crystals are filtered and Washed with ethanol and ether, and dried at 78 C. in the vacuum drier; yield, 1.6 parts melting point 154- 155 C. with gas evolution.

A mixture of 8 parts of 4-amino-l-methyl-2-pyrrole-. carboxylic acid, parts of ethanol, 200 parts of water,

Patented Mar. 12,

tiss e;

42 parts of 5N sodium hydroxide and 14 parts of henzenesulfonyl chloride is heated in a stearn bath until solution is complete. The solution is cooled and acidified (to pH 1) with concentrated hydrochloric acid. The product, 9.85 parts, is isolated after cooling (5 C.) overnight. It is purified by dissolving in dilute sodium hydroxide solution, clarifying with'charcoal and precipitating by acidification. It melts at 182.5 C. with evolution of gas. EXAMPLE 2 4-ur eid-1-mtlzyl 2-pyrr0lecarboxylic acid A s ut en f ra s wim?-ls Y1- -p r9 eca e i a sul at in 50 Pa t o W t r is about 5 parts of solid potassium cyanate. The reaction mixture is acidified with hydrochloric a, and after one half hour the precipitate is filtered. This is dissolved in ethanol, filter ed and high boiling petroleum ether added to induce crystallization. The product is obtained as white cry tals, melting point 1899 19 C. with gas evolution. a

XAMP E 3 4-{2,fl-diuitrophenyl) amino I 7 methyl -2 f pyrrolecrq boxylic acid A solution of 2 parts of 4-amino-l-methyl-Z-pyrrolecarboxylic acid sulfate in 50 parts of saturated sodium bicarbonate solution is reacted with 5 parts of 2,4-dinitrofiuorobenzene in 160 parts of ethanol with stirring for 7 EXAMPLE 4 4 -earl;0be zoxyamido-1-mcthyl-2-pyrrolccarbmylic acid Carbobenzoxychloride (6.1 parts) is added dropwise simultaneously witha'n OLlN sodium hydroxide solution (27 parts) to a chilled solution of 4-amino l-ni'ethyl2'- pyrrolecarboxylic acid .l/Zl-IzSQr (5 parts) in OLlN sodium hydroxide solution (53 parts). Thesolution is stirred for a few minutes and a small amount of insoluble solid'is filtered oil. The filtrate is acidified to Congo Red test paper with concentrated hydrochloric acid solution. After chilling'and scratching a crystalline solid forms. This is filtered and air dried to give 3 parts of 4-carbobenzoxyamido-l-methyl-2 pyrrolecarboxylic acid, melting at 138-'-l4l C. with gas evolution. l

EXAMPLE 5 Ethyl 4 (N amidinoguanidino)-1-methyl 2-pyrr0lec 1rboxylate A solution of ethyl l-methyl 4-nitro-2pyrrolecarb7o;gylate parts) in'ethanol' (ZOOTpaftjs) is'fhydiogeriatedwith palladium on carbon (4 parts) as catalyst in a Parr low pressure apparatus. The hydrogen uptake is rapid and essentially quantitative. The catalyst is'filtered and to the almost colorless filtrate is added concentrated sul furic acid (3.78 ,parts).' The suspension ifchilled and the white crystalline precipitateis filtered, washed with ether and airdried ito' givs1'4's parts (91%) ofe'thyl 4-.

react with 7 menu is passed through the refluxingsolutio oil which forms is. separated from the aqueouslayer and caused to crystallize by trituration with alcohol. The pink, crystalline powder thusi'ootained is washed well with water and dried to yield 10 partsof ethyl 4-(Nramidinos a nq).- m h l-2ryrro ecer qxy ts with t skin point or m r/'5? -c. (ea ments-e The products purified by recrystallization frozn'dilnte alcohol with the d o c r zina sar on o s te l h an .ct s a s itll a ground with water, 25 parts. The insoluble material is filtered otiand dried to give 35 parts of crude product which has a melting range of 195 -'200 C.'(wi

composition). The crude product is purified by ecr' talliz'ation from a' -largevolume of alcohol't'o give la gle,

almost white irregular' plate-like crystals ha' q melting 228 C. with decomposition. i

i EXAM LE 1 V boxylat'e hydroiodide C d e hy -me hy -t i d -pyrm ec bqxy- Ethyl-1 -metl yl-4-(S methylisozfhioureido)-2-pyrrolecar- V late, 35 parts, methyl iodide; 25 parts, and ethanol,'"f280 parts, are reflux'dtogether' foro'ne hour Evaporation of the alcohol leaves a yellow, crystalline residue of crude product, 43 parts. This material has a melting range of l86l95 C. and is water soluble. A water solution of this salt when treated with dilute ammonium hydroxide gives the base which has a melting range of 12 6- -128 C.

EXA LE Ethyl 4gumiidin0-1-methyl-z-pyrrqlecarboxylate nitrate Ethyl me y i -ts-me liso h u e )inhibi carboxylate hy d roiodide, 20parts, refluxed in ahsol alcohol;"160"part'si "A slow stream'ofanhydrou evolution of methyl mercaptan ceases."

mixture is' then iev'aporated todryness'. The resulting. H

residue, 17 'paffsfisi dissolved in water,"150 parts' in ar'rice bath'and dilute nitr'ic acid added until preci ti'on' of the'crude product is complete. Thecrude rial is purified by recrystallization "frornwa terto" give eightpa'r'tsof pure product having afme 'ng p oinfof 244 CiTwith decompositioml EXAMPLE 9- N .-,(2-garbeth0xy-1 methylpyrr0lyl-4 amidinomethylmethylpentamethyleneammonium iodide Cyanomethylmethylpentamethyleneammonium iodide (33.5 parts) is added to an ethanolic solution (200 parts) of ethyl 4-amino-1-methyl-2-pyrrolecarboxylate, prepared by catalytic hydrogenation of the corresponding nitro 7 like drystals which are collected and washedwith methyl- EXAMPLE Twenty-six parts of ethyl 1-methyl-4-amino-2-pyrrolecarboxylate dissolved in 220 parts of dimethylformamide is added to a suspension of 40 parts of methyl alphacarbobenzyloxyamino-acetthioimidate (prepared by the action of methyl mercaptan and dry hydrochloric acid upon alpha-carbobenzyloxyaminoacetonitrile in ether) in 250 parts of dimethylformamide. After a few minutes of shaking at room temperature, a clear solution results and an odor of methyl mercaptan is evident. The reaction mixture is allowed to stand at room temperature for hours and is then poured into 5000 parts of diethyl ether. The white precipitate formed is filtered off, washed with diethyl ether and dried under reduced pressure. The yield of ethyl 4-(2-carbobenzyloxyaminoacetimidoylamino)-l-methyl-2-pyrrolecarboxylate hydrochloride is 35 parts; melting point, 154156 C.

Thirty parts of finely ground ethyl 4-(2-carbobenzyloxyaminoacetimidoylamino)-l-methyl 2 pyrrolecarboxylate hydrochloride is added to 250 parts of a solution of hydrobromic acid in glacial acetic acid. A clear solution is soon obtained. On standing a few minutes, gas evolution is noted and a white precipitate commences to separate from the solution. After one and one-half hours, the reaction mixture is poured into 2500 parts of diethyl ether, and the mixture allowed to stand at room temperature overnight. The precipitate is then filtered ofi, washed with diethyl ether and dried under reduced pressure over solid sodium hydroxide. The yield of ethyl 4- (2-aminoacetimidoylamino)-1- methyl-Z-pyrrolecarboxylate dihydrobromide is twentyfive parts; melting point 265 -267 C. with decomposition.

6 We claim: 1. Compounds of the group having the general formula:

in which R is a lower alkyl radical, R is a member of the group consisting of amidino, amidinoamidino, aminoacetimidoyl, thiocarbamoyl, S-lower alkylisothiocarbamoyl, carbamoyl, carbobenzoxy, nitrophenyl, and phenylsulfonyl radicals and Z is a member of the group consisting of hydroxyl and alkoxyl radicals.

2. An ethyl l-lower alkyl 4-aminoacetimidoylamino-2- pyrrolecarboxylate.

3. A lower alkyl ester of l-methyl 4-aminoacetimidoylamino-Z-pyrrolecarboxylic acid.

4. Ethyl 4-guanidino-1-methyl-Z-pyrrolecarboxylate.

5. 4-ureido-1-methylpyrrole-Z-carboxylic acid.

6. Ethyl l-methyl-4-aminoacetimidoylamino-Z-pyrrolecarboxylate.

7. 4 carbobenzoxyamido-l-methyl-Z-pyrrolecarboxylic acid.

8. Ethyl 4-(N-amidinoguanidino)-1-methyl-2-pyrrolecarboxylate.

References Cited in the file of this patent 

1. COMPOUNDS OF THE GROUP HAVING THE GENERAL FORMULA: 